Spatial and Temporal Dynamics of vWF Gene Expression

项目总结（见说明）： 血管性血友病因子（vWF）是一种特异性表达于内皮细胞和巨核细胞的促凝血因子。初步研究表明vWF基因调控的几个有趣的功能。首先，与动脉相比，vWF优先在静脉中表达，并且与动脉流相比，培养的EC暴露于静脉流导致vWF表达的更高表达。一下vWF在来自不同器官的EC中的表达由不同的DNA启动子元件介导。第三，脓毒症与vWF蛋白循环水平升高相关，但vWF转录普遍受到抑制，这一效应可通过ETS因子ERG的转录活性降低来解释。基于这一背景，总体假设是vWF表达在空间和时间上受到涉及血流动力学力、血管床/器官特异性转录模块和ETS因子的机制的调节。目的1将测试的假设，动脉-静脉vWF表达的差异是由流量介导的。目的2将测试的假设，vWF启动子包含c/s-调控元件，直接血管床特异性基因表达的毛细血管和静脉的心脏和骨骼肌。目的3将检验内毒素血症中vWF的抑制是由ERG活性介导的假设。

PROJECT SUMMARY (See instructions): Von Willebrand factor (vWF) is a procoagulant that is expressed specifically in endothelial cells (ECs) and megakaryocytes. Preliminary studies demonstrate several interesting features of vWF gene regulation. First, vWF is preferentially expressed in veins compared with arteries and exposure of cultured ECs to venous flow results in higher expression of vWF expression compared with arterial flow. Second. vWF expression in ECs from different organs is mediated by distinct DNA promoter elements. Third, sepsis is associated with increased circulating levels of vWF protein, yet widespread repression of vWF transcription, an effect that may be explained by reduced transcriptional activity of the ETS factors, ERG. Based upon this background, the overall hypothesis is that vWF expression is spatially and temporally regulated by mechanisms that involve hemodynamic forces, vascular bed/organ-specific transcriptional modules and the ETS factor. Aim 1 will test the hypothesis that arterial-venous differences in vWF expression are mediated by flow. Aim 2 will test the hypothesis that the vWF promoter contains c/s-regulatory elements that direct vascular bed-specific gene expression in the capillaries and veins of heart and skeletal muscle. Aim 3 will test the hypothesis that the repression of vWF in endotoxemia is mediated by ERG activity.